Follis Ariele Viacava, Llambi Fabien, Merritt Parker, Chipuk Jerry E, Green Douglas R, Kriwacki Richard W
Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Mol Cell. 2015 Aug 20;59(4):677-84. doi: 10.1016/j.molcel.2015.06.029. Epub 2015 Jul 30.
The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response.
肿瘤抑制因子p53的胞质部分激活凋亡效应蛋白BAX以触发细胞凋亡。在此我们报告,p53通过一种不同于仅由BH3蛋白(BIM和BID)激活所涉及的机制来激活BAX。我们观察到,p53内脯氨酸47(Pro47)的顺反异构化(一种固有的罕见分子事件)是BAX激活所必需的。脯氨酰异构酶Pin1通过催化p53 Pro47的顺反互变来增强p53依赖性的BAX激活。我们的结果揭示了一种信号传导机制,即一种蛋白质中的脯氨酸顺反异构化触发下游信号传导伙伴的构象和功能变化。通过胞质p53和Pin1的协同作用激活BAX可能整合细胞应激信号以诱导直接的凋亡反应。